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Sponsor's decision due to negative result of Phase 3 study TH-CR-406/SARC021
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| Name | Class |
|---|---|
| Threshold Pharmaceuticals | INDUSTRY |
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This is a Phase 2, single-arm, Japanese multicenter trial to evaluate the safety, tolerability, and efficacy of TH-302 in combination with doxorubicin in subjects with locally advanced unresectable or metastatic soft tissue sarcoma (STS).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| TH-302 and doxorubicin | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| TH-302 | Drug | TH-302 will be administered at a dose of 300 milligram per square meter (mg/m^2) by intravenous infusion over 30 minutes on Days 1 and 8 of every 21-day cycle until the evidence of significant treatment-related toxicity or progressive disease. |
| Measure | Description | Time Frame |
|---|---|---|
| Progression Free Survival (PFS) by Independent Central Review (Phase II Treatment Period) | PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | From first dose of study drug administration until PD or death, evaluated at 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Progression Free Survival (PFS) by Investigator Review (Phase II Treatment Period) | PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Responsible | Merck Serono Co., Ltd., Japan | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site | Kashiwa | Japan | ||||
| Research Site |
The study was planned to include a combination therapy period (including an initial Safety Run-In Phase followed by Phase II treatment period) and a TH-302 monotherapy period. However, due to early termination, only Safety Run-In Phase was conducted; thus, all the analyses are limited to Safety Run-In Phase.
First/Last subject (informed consent): 10 December 2014/02 November 2015. Study completion date: 12 January 2016. Clinical data cut-off: 31 March 2016.
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| ID | Title | Description |
|---|---|---|
| FG000 | TH-302 and Doxorubicin | Subjects received TH-302 at a dose of 300 milligram per square meter (mg/m^2) by intravenous infusion over 30 minutes on Day 1 and 8 of every 21-day cycle and Doxorubicin at a dose of 75 mg/m^2 by intravenous injection (over at least 5 minutes) or by intravenous infusion over 6-96 hours on Day 1 of every 21-day cycle starting 2 to 4 hours after completion of TH-302 administration until the evidence of significant treatment-related toxicity or progressive disease. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Safety Analysis Set (SAF) included all subjects who received at least 1 dose of either TH-302 or doxorubicin.
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| ID | Title | Description |
|---|---|---|
| BG000 | TH-302 and Doxorubicin | Subjects received TH-302 at a dose of 300 milligram per square meter (mg/m^2) by intravenous infusion over 30 minutes on Day 1 and 8 of every 21-day cycle and Doxorubicin at a dose of 75 mg/m^2 by intravenous injection (over at least 5 minutes) or by intravenous infusion over 6-96 hours on Day 1 of every 21-day cycle starting 2 to 4 hours after completion of TH-302 administration until the evidence of significant treatment-related toxicity or progressive disease. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Progression Free Survival (PFS) by Independent Central Review (Phase II Treatment Period) | PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study | Posted | From first dose of study drug administration until PD or death, evaluated at 6 months |
|
Baseline up to Day 210 (Safety Run-In Phase)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | TH-302 and Doxorubicin | Subjects received TH-302 at a dose of 300 milligram per square meter (mg/m^2) by intravenous infusion over 30 minutes on Day 1 and 8 of every 21-day cycle and Doxorubicin at a dose of 75 mg/m^2 by intravenous injection (over at least 5 minutes) or by intravenous infusion over 6-96 hours on Day 1 of every 21-day cycle starting 2 to 4 hours after completion of TH-302 administration until the evidence of significant treatment-related toxicity or progressive disease. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pneumonia | Infections and infestations | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Infection | Infections and infestations | Non-systematic Assessment |
This study was terminated early following the discontinuation of TH-302 clinical development program. Only 6 subjects were enrolled and treated in the Safety Run-In Phase; thus, the statistical analyses are limited to the Safety Run-In Phase.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Merck KGaA Communication Center | Merck Healthcare, a business of Merck KGaA, Darmstadt, Germany | +49-6151-72-5200 | service@merckgroup.com |
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| ID | Term |
|---|---|
| D012509 | Sarcoma |
| ID | Term |
|---|---|
| D018204 | Neoplasms, Connective and Soft Tissue |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| C552526 | TH 302 |
| D004317 | Doxorubicin |
| ID | Term |
|---|---|
| D003630 | Daunorubicin |
| D018943 | Anthracyclines |
| D009279 | Naphthacenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
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| Doxorubicin | Drug | Doxorubicin will be administered at a dose of 75 mg/m^2 by intravenous injection (over at least 5 minutes) or by intravenous infusion over 6-96 hours on Day 1 of every 21-day cycle starting 2 to 4 hours after completion of TH-302 administration until the evidence of significant treatment-related toxicity or progressive disease. |
|
| From first dose of study drug administration until PD or death, evaluated at 6 months |
| Progression-free Survival (PFS) by Investigator and Independent Central Review (Phase II Treatment Period) | PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | From first dose of study drug administration until PD or death, evaluated at 3 months and 9 months |
| Progression-free Survival (PFS) (Phase II Treatment Period) | PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | From first dose of study drug administration until PD or death, assessed up to 12 months |
| Best Overall Response (BOR) by Independent Central Review (Phase II Treatment Period) | BOR was planned to be determine according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as adjudicated by an Independent Central Review. BOR is defined as the best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression or recurrence (taking the smallest measurement recorded since start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or appearance of 1 or more new lesions. | From first dose of study drug administration until PD or death, assessed up to 12 months |
| Best Overall Response (BOR) by Investigator (Phase II Treatment Period) | BOR was planned to be determine according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as adjudicated by an Independent Central Review. BOR is defined as the best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression or recurrence (taking the smallest measurement recorded since start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or appearance of 1 or more new lesions. | From first dose of study drug administration until PD or death, assessed up to 12 months |
| Duration of Response (Phase II Treatment Period) | Duration of response according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) is defined as the time from the first assessment of complete response (CR) or partial response (PR) until the date of the first occurrence of progressive disease (PD), or until the date of death. CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to less than (<) 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | From first dose of study drug administration until PD or death, assessed up to 12 months |
| Overall Survival (OS) (Phase II Treatment Period) | OS is defined as the time from first dose to death due to any cause. | From first dose of study drug administration until the last subject completes the survival follow-up, assessed up to 12 months |
| Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) (Safety Run-In Phase) | An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the stud drug. | From baseline until end of trial, assessed up to Day 210 |
| Tokyo |
| Japan |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
|
| Secondary | Progression Free Survival (PFS) by Investigator Review (Phase II Treatment Period) | PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study | Posted | From first dose of study drug administration until PD or death, evaluated at 6 months |
|
|
| Secondary | Progression-free Survival (PFS) by Investigator and Independent Central Review (Phase II Treatment Period) | PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study | Posted | From first dose of study drug administration until PD or death, evaluated at 3 months and 9 months |
|
|
| Secondary | Progression-free Survival (PFS) (Phase II Treatment Period) | PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study | Posted | From first dose of study drug administration until PD or death, assessed up to 12 months |
|
|
| Secondary | Best Overall Response (BOR) by Independent Central Review (Phase II Treatment Period) | BOR was planned to be determine according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as adjudicated by an Independent Central Review. BOR is defined as the best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression or recurrence (taking the smallest measurement recorded since start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or appearance of 1 or more new lesions. | As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study | Posted | From first dose of study drug administration until PD or death, assessed up to 12 months |
|
|
| Secondary | Best Overall Response (BOR) by Investigator (Phase II Treatment Period) | BOR was planned to be determine according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as adjudicated by an Independent Central Review. BOR is defined as the best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression or recurrence (taking the smallest measurement recorded since start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or appearance of 1 or more new lesions. | As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study | Posted | From first dose of study drug administration until PD or death, assessed up to 12 months |
|
|
| Secondary | Duration of Response (Phase II Treatment Period) | Duration of response according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) is defined as the time from the first assessment of complete response (CR) or partial response (PR) until the date of the first occurrence of progressive disease (PD), or until the date of death. CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to less than (<) 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study | Posted | From first dose of study drug administration until PD or death, assessed up to 12 months |
|
|
| Secondary | Overall Survival (OS) (Phase II Treatment Period) | OS is defined as the time from first dose to death due to any cause. | As the study was terminated early following the discontinuation of the TH-302 clinical development program, it was decided as per Statistical Analysis Plan not to collect and evaluate the efficacy data for this study | Posted | From first dose of study drug administration until the last subject completes the survival follow-up, assessed up to 12 months |
|
|
| Secondary | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) (Safety Run-In Phase) | An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the stud drug. | The SAF Analysis Set included all subjects who received at least 1 dose of either TH-302 or doxorubicin. | Posted | Number | Subjects | From baseline until end of trial, assessed up to Day 210 |
|
|
|
| 4 |
| 6 |
| 6 |
| 6 |
| Tumour haemorrhage | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Non-systematic Assessment |
|
| Febrile neutropenia | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Lymph gland infection | Infections and infestations | Non-systematic Assessment |
|
| Tumour pain | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Non-systematic Assessment |
|
| Anaemia | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Febrile neutropenia | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Hypoalbuminaemia | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Hyponatraemia | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Hypophosphataemia | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Dysgeusia | Nervous system disorders | Non-systematic Assessment |
|
| Dysphonia | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | Non-systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Non-systematic Assessment |
|
| Alopecia | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Palmar-plantar erythrodysaesthesia syndrome | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Proteinuria | Renal and urinary disorders | Non-systematic Assessment |
|
| Fatigue | General disorders | Non-systematic Assessment |
|
| Infusion site reaction | General disorders | Non-systematic Assessment |
|
| Pyrexia | General disorders | Non-systematic Assessment |
|
| Blood alkaline phosphatase increased | Investigations | Non-systematic Assessment |
|
| C-reactive protein increased | Investigations | Non-systematic Assessment |
|
| Electrocardiogram QT prolonged | Investigations | Non-systematic Assessment |
|
| Gamma-glutamyltransferase increased | Investigations | Non-systematic Assessment |
|
| Lymphocyte count decreased | Investigations | Non-systematic Assessment |
|
| Neutrophil count decreased | Investigations | Non-systematic Assessment |
|
| Platelet count decreased | Investigations | Non-systematic Assessment |
|
| White blood cell count decreased | Investigations | Non-systematic Assessment |
|
| Incorrect dosage administered | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Infusion related reaction | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
Not provided
| D006841 |
| Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |
| D000617 | Aminoglycosides |
| D006027 | Glycosides |
| D002241 | Carbohydrates |